Earlier today, our Encycle team had a discussion regarding some of the issues pertaining to N-Me amino acid coupling reactions. Overall, we typically have no trouble introducing N-Me groups into peptides. All we need is an appropriately protected N-Me building block for the solid-phase Fmoc chemistry and off we go. The trouble is, sometimes this coupling fails miserably if hindered amino acids are brought together. There is an ingeneous solution to the problem and it offers a workaround. The reaction was developed by Professor Schafmeister of Temple University and it involves amino acid fluorides as electrophiles. A few words about them: in brief, acid fluorides are remarkably stable to aqueous hydrolysis. In contrast to their chloride congeners, fluorides also resist racemization. One of the classic ways to prepare them is through the use of DAST (there are better alternatives these days). Kaduk’s way cited below is as simple as it gets – just mix an Fmoc-protected amino acid with DAST in dichloromethane and get your acid fluoride product after aqueous work-up. The product can be crystallized from dichloromethane/hexanes, which makes for a rather practical method.
Back to the hindered amide workaround developed by Schafmeister. The mechanism involves mixed anhydride formation, which is the central trick here. Once this electrophilic intermediate has been formed, the rest is “downhill history” as nitrogen acylation becomes an intramolecular process. Even exceptionally hindered amides can be made using this procedure. Connoisseurs of multicomponent reaction might notice a similarity with Ugi’s mixed anhydride. We are attempting to run the Schafmeister process this week (wish us luck, we have a tough substrate that failed with everything else).